Qu Xiaoyu, Gao Huan, Tao Lina, Zhang Yueming, Zhai Jinghui, Sun Jingmeng, Song Yanqing, Zhang Sixi
Department of Pharmacy, the First Hospital of Jilin University, China.
Changchun University of Chinese Medicine, China.
J Toxicol Sci. 2019;44(3):167-175. doi: 10.2131/jts.44.167.
The aim of this study was to explore the role of the NOD-like receptor family, pyrin domain containing (NLRP3) inflammasome and autophagy in Astragaloside IV (AS IV)-mediated protection against cisplatin-induced liver and kidney injury in rats. Rats were intraperitoneally administered cisplatin at a dose of 15 mg/kg and orally administered AS IV for 7 days. Histopathological and biochemical analysis were used to assess liver and kidney function. The levels and localization of NLRP3 and autophagy-associated protein were determined by Western blot and immunohistochemistry. Intraperitoneal administration of cisplatin induced acute liver and kidney injury, and activated the NLRP3 inflammasome. Oral administration of AS IV for 7 days protected against the cisplatin-induced injury, and inhibited the expression of NLRP3, as well as the production of pro-inflammatory cytokines. Moreover, cisplatin modulated the conversion of LC3 II and the expression of p62, thereby inhibiting autophagy and the activation of NLRP3. AS IV effectively protected against cisplatin-induced injury by inducing autophagy and limiting the expression of NLRP3. Autophagy-mediated NLRP3 inhibition might play a crucial role in AS IV-mediated protection against cisplatin-induced toxicity. These results provide evidence of a novel therapeutic that may be used to alleviate the toxic effects of platinum-based chemotherapy.
本研究旨在探讨含吡喃结构域的NOD样受体家族（NLRP3）炎性小体和自噬在黄芪甲苷（AS IV）介导的对顺铂诱导的大鼠肝损伤和肾损伤保护作用中的作用。大鼠腹腔注射15 mg/kg剂量的顺铂，并口服AS IV 7天。采用组织病理学和生化分析评估肝肾功能。通过蛋白质免疫印迹法和免疫组织化学法测定NLRP3和自噬相关蛋白的水平及定位。腹腔注射顺铂可诱导急性肝损伤和肾损伤，并激活NLRP3炎性小体。口服AS IV 7天可预防顺铂诱导的损伤，并抑制NLRP3的表达以及促炎细胞因子的产生。此外，顺铂调节LC3 II的转化和p62的表达，从而抑制自噬和NLRP3的激活。AS IV通过诱导自噬和限制NLRP3的表达有效预防顺铂诱导的损伤。自噬介导的NLRP3抑制可能在AS IV介导的对顺铂诱导的毒性保护中起关键作用。这些结果为一种可用于减轻铂类化疗毒性作用的新型治疗方法提供了证据。
